Exaggerated hepatotoxicity of acetaminophen in mice lacking tumor necrosis factor receptor-1: Potential role of inflammatory mediators

Carol R. Gardner, Jeffrey D. Laskin, Donna M. Dambach, Hawjyh Chiu, Stephen K. Durham, Peihong Zhou, Mary Bruno, Donald R. Gerecke, Marion K. Gordon, Debra L. Laskin

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

Transgenic mice with a targeted disruption of the tumor necrosis factor receptor 1 (TNFR1) gene were used to analyze the role of TNF-α in pro- and anti-inflammatory mediator production and liver injury induced by acetaminophen. Treatment of wild-type mice with acetaminophen (300 mg/kg) resulted in centrilobular hepatic necrosis. This was correlated with expression of inducible nitric oxide synthase (NOS II) and nitrotyrosine staining of the liver. Expression of macrophage chemotactic protein-1 (MCP-1), KC/gro, interleukin-1β (IL-1β), matrix metalloproteinase-9 (MMP-9), and connective tissue growth factor (CTGF), inflammatory mediators known to participate in tissue repair, as well as the anti-inflammatory cytokine, interleukin-10 (IL-10), also increased in the liver following acetaminophen administration. TNFR1-/- mice were found to be significantly more sensitive to the hepatotoxic effects of acetaminophen than wild-type mice. This was correlated with more rapid and prolonged induction of NOS II in the liver and changes in the pattern of nitrotyrosine staining. Acetaminophen-induced expression of MCP-1, IL-1β, CTGF, and MMP-9 mRNA was also delayed or reduced in TNFR1-/- mice relative to wild-type mice. In contrast, increases in IL-10 were more rapid and more pronounced. These data demonstrate that signaling through TNFR1 is important in inflammatory mediator production and toxicity induced by acetaminophen.

Original languageEnglish (US)
Pages (from-to)119-130
Number of pages12
JournalToxicology and Applied Pharmacology
Volume192
Issue number2
DOIs
StatePublished - Oct 15 2003

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Pharmacology

Keywords

  • Acetaminophen
  • Liver
  • Nitric oxide
  • TNF-α
  • TNFRI
  • Tissue repair

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